Targeting of neurotransmitter receptors to synapses is essential for efficient synaptic transmission and plays an important role in the regulation of synaptic plasticity in the brain. AMPA receptors are the major excitatory neurotransmitter receptors in the central nervous system. We have identified several PDZ domain-containing proteins that specifically interact with AMPA receptors and are critical for the regulation of AMPA receptor membrane trafficking and synaptic plasticity. Several of these proteins, including GRIP1 and GRIP2 (Glutamate Receptor Interacting Proteins) and PICK1 (Protein Interactor with C Kinase), specifically interact with the C-terminal domains of the AMPA receptor subunits. We have found that these interactions are dynamically regulated by protein phosphorylation of the receptor subunits. We have identified additional members of this protein complex, including NSF, GRASP1, KIBRA, WWC2 and SNX27, which are involved in the regulation of AMPA receptor membrane trafficking. Interestingly, genetic variants of these proteins have recently been associated with several cognitive disorders. In this research proposal we plan to use several complementary approaches to further characterize the structure and function of this PDZ based membrane trafficking complex and determine its role in AMPA receptor synaptic targeting, synaptic plasticity and cognitive behavior. In complementary experiments, we will use knockout and knockin mice of this complex to elucidate the role of the PDZ domain-based receptor complexes in several forms of plasticity in the hippocampus, cerebellum, amygdala, somatosensory and visual cortex. Finally, we will analyze behavioral phenotypes, including spatial and motor learning and fear conditioning and extinction, in these knockout and knockin mice to determine the role of these regulatory mechanisms in higher brain processes.